The present invention relates to novel 1,2,4-triazin-3,5-dione compounds, in particular to the compounds of the formula I as described herein. The compounds possess valuable therapeutic properties and are suitable, in particular, for treating diseases that respond to modulation of the dopamine D3 receptor.
Neurons obtain their information by way of G protein-coupled receptors, inter alia. A large number of substances exert their effect by way of these receptors. One of them is dopamine. Confirmed findings exist with regard to the presence of dopamine and its physiological function as a neurotransmitter. Disorders in the dopaminergic transmitter system result in diseases of the central nervous system which include, for example, schizophrenia, depression and Parkinson's disease. These diseases, and others, are treated with drugs which interact with the dopamine receptors.
Up until 1990, two subtypes of dopamine receptor had been clearly defined pharmacologically, termed D1 and D2 receptors. More recently, a third subtype was found, namely, the D3 receptor which appears to mediate some effects of antipsychotics and antiparkinsonian drugs (J. C. Schwartz et al., “The Dopamine D3 Receptor as a Target for Antipsychotics” in Novel Antipsychotic Drugs, H. Y. Meltzer, ed., Raven Press, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging 1998, 12:495-514; J. N. Joyce, Pharmacology and Therapeutics 2001, 90:231-59, “The Dopamine D3 Receptor as a Therapeutic Target for Antipsychotic and Antiparkinsonian Drugs”). Since then, the dopamine receptors have been divided into two families. On the one hand, there is the D2 group, consisting of D2, D3 and D4 receptors, and, on the other hand, the D1 group, consisting of D1 and D5 receptors.
Whereas D1 and D2 receptors are widely distributed, D3 receptors appear to be expressed regioselectively. Thus, these receptors are preferentially to be found in the limbic system and the projection regions of the mesolimbic dopamine system, especially in the nucleus accumbens, but also in other regions, such as the amygdala. Because of this comparatively regioselective expression, D3 receptors are regarded as being a target having few side-effects and it is assumed that while a selective D3 ligand would have the properties of known antipsychotics, it would not have their dopamine D2 receptor-mediated neurological side-effects (P. Sokoloff et al., Arzneim. Forsch./Drug Res. 42(1):224 (1992), “Localization and Function of the D3 Dopamine Receptor”; P. Sokoloff et al., Nature, 347:146 (1990), “Molecular Cloning and Characterization of a Novel Dopamine Receptor (D3) as a Target for Neuroleptics”).
Heterocyclic compounds having an affinity for the dopamine D3 receptor have been described previously on various occasions, as for example in WO 96/02246, WO 96/02519, WO 96/02520, WO 99/02503, WO 2004/080981, WO2004/108706, WO 2005/118558, WO 2005/118571 and WO 2006/015842. These compounds possess high affinities for the dopamine D3 receptor, and have therefore been proposed as being suitable for treating diseases of the central nervous system. Unfortunately, their selectivity towards the D3 receptor is not always satisfactory. Moreover, some of these compounds have an unfavorable DMPK profile (DMPK: metabolic stability and pharmacokinetics), in particular in terms of microsomal stability and in vivo half-life or a poor bioavailability. Consequently there is an ongoing need to provide new compounds, which have an improved selectivity towards D3 receptors or an improved pharmacological profile, such as a favorable DMPK profile, and/or a high bioavailability.
U.S. Pat. No. 5,977,106 describes 1,2,4-triazin-3,5-dione compounds which are ligands towards the serotoninergic 5HT1 receptor.